Follistatin is a single-chain glycoprotein of 35 kDa which is composed of four cysteine-rich domains, three of which are homologous and highly conserved. (Lane et al. (1994) The FASEB Journal 8:163-173; Esch et al. (1987) Mol. Endo. 1:849-855; Sugano et al. (1994) Frontiers in Endocrinology Vol. 3: Inhibin and Inhibin-related Proteins, Rome: Ares-Serono Symposia, 69-80). Follistatin domains have recently been described in several mosaic proteins, including agrin (Rupp et al. (1991) Neuron 6:811-823), osteonectin/SPARC (Lankat-Buttgereit et al. (1988) FEBS Lett. 236:352-356), and the brain-specific extracellular matrix glycoprotein, SC1 (Johnston et al. (1990) Neuron 2: 165-176; see also, Patthy et al. (1993) Trends Neurosci. 16:76-81). It has been proposed that modules donated to mosaic proteins retain the function they had in the donor protein. (Eib et al. (1996) J. Neurochem. 67(3) 1047-1055).
Follistatin binds the transforming growth factor-.beta. (TGF-.beta.) family members activin-A and inhibin. (Michel et al. (1993) Molecular and Cellular Endocrinology 91:1-11). The family of TGF-.beta. proteins includes, among others, activin-A and inhibin. (Eib et al. (1996) J. Neurochem. 67:1047-1055). Members of the TGF-.beta. family are multifunctional cytokines with physiological effects on the growth and differentiation of a variety of normal and neoplastic cells (Sporn et al. (1992) J. Cell. Biol. 119:1017-1021). It has been proposed that follistatin and other follistatin-related molecules act by regulating the availability of TGF-.beta.-related and/or other growth factors thereby influencing cellular migration, proliferation, and differentiation (Amthor (1996) Dev. Biol. 178:343-361).
Follistatin and follistatin-related molecules have been found to modulate a variety of biological processes. For example, follistatin has been identified as a regulator of pituitary follice stimulating hormone (FSH) secretion (Ueno et al. (1990) Progress in Growth Factor Research 2:113-124; Besecke et al. (1997) Endocrinology 138:2841-2848). Follistatins have also been characterized as growth factors (Vale et al. (1988) Recent Progress in Hormone Research 44:1-34; Link et al. (1997) Experimental Cell Research 233:350-362), and embryo modulators (Huylebroeck et al. (1994) Frontiers in Endocrinology, Vol. 3: Inhibin and Inhibin-related Proteins, Rome: Ares-Serono Symposia Publications, 271-288; Petraglia (1996)). Osteonectin, which contains a single follistatin domain, binds the platelet-derived growth factor (PDGF), preventing PDGF receptor activation (Raines et al. (1992) Proc. Natl. Acad. Sci. 89:1281-1304). Also, the follistatin domains in agrin have been reported to act in binding and thus creating local concentrations of TGF-.beta. family members in motor neurons and muscle (Patthy et al. (1993)). In addition, follistatin has high affinity for heparin sulfate side chains of membrane proteoglycans. (Nakamura et al. (1991) J. Biol. Chem. 266:19432-19437).